Malignant tumors have become one of the main diseases that threaten human health and survival. The conventional therapies of tumor such as surgical operation, radiation therapy and chemotherapy involve external forces, which include exscinding tumors directly, killing tumor cells with radiation, or by chemotherapeutics. Chemotherapy and radiation therapy usually are unable to resolve the issues like tumor metastasis and recurrence. Moreover, these treatments always have severe toxic effects and damage the normal cells. In particular, radiation therapy and chemotherapy will damage the immune system, especially cell-mediated immunity which plays an important role in the body's anti-tumor defense. Increasing attention has been paid to biological treatments which are based on immunotherapy and promoted by the developments of modern oncology, molecular biology, theoretical immunology, biotechnology, and genetic engineering technology. Biological therapy, originally used to fight against cancers, also plays an important role in the prevention and treatment of infections, immunodeficiency, autoimmune diseases, etc., even in transplant rejection and anti-aging.
Cancer biotherapy, by means of various bioactive agents and methods, can stimulate, activate and regulate the body's immune and anti-cancer functions so the body can inhibit or even eliminate the growth of tumor cells, which shows great potential in therapeutics.
The investigation and development of a therapeutic cancer vaccine is a great challenge. Presently, satisfactory therapeutic cancer vaccines which can treat tumors or tumor cells effectively have still not been obtained, and thus patients' survival time cannot be prolonged significantly and tumors cannot be killed reliably.
In order to establish an effective vaccine for active specific immunotherapy, several obstacles must be overcome. Firstly, due to the poor specificities of tumor antigens or large tumor burdens, and patients' overall immunodeficiency caused by pre-chemotherapy as well as other factors, it is very difficult to induce the immune response of active specific immunotherapy which aims at tumor antigens. Secondly, because the antigenicity of tumor cells (particularly the immunogenicity of human spontaneously occurred tumors) is generally very weak, it may be not easy for the vaccine immunization to induce an adequate immune response to shrink the tumor. Thirdly, because of the heterogeneity in the expression of the tumor antigen, most patients need to be immunized by various antigens simultaneously. Fourthly, one of the main problems of developing a cancer vaccine is that it is hard to build an ideal animal model which is similar to the patients' clinical situation.
Although passive specific immunotherapy, namely transferring sensitized tumor-specific T lymphocytes, can treat the tumor of experimental animals effectively (confirmed in the late 60s and the early 70s), many issues including insufficient sensitized T lymphocytes, the difficulty of rejection reaction to be induced due to the weakness of antigens of the spontaneous tumors, and the incompatibility of sensitized T lymphocytes obtained from animal experiments for humans, hinder the study and the treatment of sensitized T lymphocytes. The biggest problem for the application of adoptive cellular immune therapy is how to obtain sufficient sensitized tumor-specific T lymphocytes.
Active non-specific immunity can stimulate the immune system by non-specific stimulation to enhance non-specific immune reactions; it can improve the immune reactions to existing tumors. The majority of active non-specific immunotherapy applied on humans in the past is not successful and most of them have not been used today. Almost all of the active non-specific treatments for patients who had advanced cancers are unsuccessful.
Passive non-specific immunotherapy, such as LAK/IL-2 and TIL/TDAK (tumor-derived activated killing cells) therapies, mainly aims at killing tumor cells by means of infusing their autologous or allogenic non-specific effectors. However, the effectiveness of these therapies are limited and need to be improved. For example, patients' insufficient autologous LAK precursor cells, along with slow amplification and limited efficacy, all lead to the ineffectiveness of the treatment. Moreover, patients usually cannot tolerate it due to serious side effects brought upon by repeated applications of high-dose rIL-2. The biggest disadvantages of TDAK therapy (which are more obvious than that of LAK therapy) are that it is time-consuming, laborious, and costly. The activity of TIL depends on the type, size and the extent of necrosis of the tumor, and not all tumors are infiltrated by lymphocytes. As a matter of fact, in most tumors it is difficult to obtain autologous tumor-specific TIL. The proliferative capability and anti-tumor activity of TIL will be reduced along with prolonged couture time. In addition, apoptosis can be found in some of the cells in the course of the cell culture. The TIL obtained from the tumors that produce immunosuppressive factors may be unable to proliferate, similar to the TIL obtained from metastatic tumors. In view of this, how to achieve these high tumor-reactive lymphocyte subsets and amplify them in vitro becomes the important issue of TIL/TDAK.
Therefore, it is urgent to develop a new concept and adopt a new approach to prepare cancer vaccines and to overcome the various problems associated with current immune therapies mentioned above.